This invention relates to the fields of pharmaceutical and organic chemistry and provides a new process for preparing intermediates useful for the preparation of cryptophycin compounds.
An efficient totally synthetic process for the preparation of useful cryptophycin compounds is desired for commercial production of such cryptophycin compounds which have been found to have antimicrotubulin properties.
The processes claimed herein provide important elements needed for an efficient total synthetic route for preparing useful cryptophycin compounds and intermediates. 4-Hydroxy-5,6-dihydropyran-2-one and derivatives thereof are important intermediates for a number of natural products; D. Seebach et al., Angew. Chem. Int. Ed. 13, 77 (1974); R. M. Carlson et al., J. Org. Chem. 40, 1610 (1975). Additionally, this series of compounds has been used for the synthesis of pharmaceuticals, for example, the drug tetrahydrolipstatin ("THL"); J. J. Landi, Jr. et al., Tetrahedron Lett., 34, 277 (1993); U.S. Pat. No. 4,598,089. Current art teaches that in order to form a carbon--carbon bond at the terminal (4-) position of an acylacetate, two equivalents of strong base, for example sodium hydride or n-butyl lithium, in an aprotic solvent must be used to deprotonate both the 2- and 4- positions, proceeding through selective alkylation of a dianion with one equivalent of electrophiles; S. M. Huckin et al., Can. J. Chem. 52, 2157 (1974); S. M. Huckin et al., J. Am. Chem. Soc. 96, 1082 (1974); N. Petragnani et al., Synthesis, 521, 78 (1982); J. R. Peterson et al., Syn. Commun. 18, 949 (1988); D. Seebach et al., Angew. Chem. 86, 40 (1974); H. Kashihara et al., Chem. Pharm. Bull. 34, 4527 (1986).
However, even under such harsh conditions, paraformaldehyde or formaldehyde have been poor electrophiles and product yield has been low. In fact, a toxic reagent, PhCH.sub.2 OCH.sub.2 Cl has been used instead of paraformaldehyde for this purpose in a multistep synthesis; E. C. Taylor et al., J. Org. Chem. 50, 5223 (1985).
The present invention provides a novel process for the preparation of lactone derivatives in high yield using simple aldehydes or ketones and less than two equivalents of base and more than one equvalent of aldehyde.
The present invention further provides novel intermediates useful in the preparation of cryptophycin compounds or other pharmaceutical agents, such as THL.